Impact of the anti-diabetic drug metformin on tumor growth «in vivo»
Notice bibliographique
Résumé
The prevalence of obesity is rapidly increasing in affluent countries and in many urban areas of the developing world. Epidemiologic studies have associated obesity with increased burden of many cancer types but the mechanisms by which obesity induces transformation or promotes neoplastic growth remain to be fully elucidated. Possible mediators include insulin, free fatty acids, increased bio-availability of steroid hormones and inflammation. It is important to gain better understanding of the relationship between these diseases as new insights may provide new opportunities for cancer prevention and treatment. Metformin, a biguanide, is a drug often prescribed for treatment of type II diabetes. Recent retrospective epidemiologic data comparing diabetics taking metformin to diabetics taking other therapies suggests that metformin may reduce the risk of developing cancer or the risk of dying from cancer. These data contribute to the rationale for research to study the physiologic links between cancer and diabetes. Preliminary laboratory work has shown that metformin is an indirect activator of AMPK via its inhibitory action on oxidative phosphorylation in the mitochondria. AMPK is a sensor of cellular energy supply and activation of this serine/threonine kinase leads to inhibition of gluconeogenesis in the liver and reduced cell proliferation in transformed cells. We wished to expand these studies by using an in vivo model of cancer and diet-induced hyperinsulinemia in order to determine if metformin has anti-neoplastic action and if so, if the indirect (insulin lowering) systemic action of metformin or the direct AMPK mediated effect on neoplastic cells is responsible. We used mouse models of diet induced hyperinsulinemia by providing a high energy/high fat diet and a control diet ad lib in order to induce the desired metabolic phenotypes. As described in Chapter II, our results reveal that metformin attenuated the stimulatory effect of the high energy diet on growth of LLC1 carcinoma in vivo while having no effect on tumor growth in mice consuming a control diet. This suggested that the indirect, insulin lowering, effects of metformin played an important role in the attenuation of tumor burden, and these effects might be independent of AMPK activation in neoplastic cells. In Chapter III we show that the effects of diet and metformin on tumor growth described in Chapter II are reproducible in another cell line, MC38 colon carcinoma. In addition to the observed effects of metformin on tumor growth, we report that metformin reduced the cleavage of SREBP-1 and the expression of fatty acid synthase in MC38 colon carcinoma. The results presented in Chapters II and III did not separate the 'direct' from the 'indirect' effects of metformin on the attenuation of tumor growth. We address this problem in Chapter IV where we present data from an experiment that allowed us to study these effects independently by using cancer cell lines engineered to be insensitive to the 'direct' AMPK-mediated effects of metformin, grown in mice that were sensitive to metformin. We used shRNA to the decrease expression of LKB1 in two cancer cell lines and observed that these cells were resistant to metformin in vitro but were sensitive to metformin in vivo when grown in animals on either a high fat or control diet. Further analysis revealed that the loss of LKB1, a known tumor suppressor and activator of AMPK, may sensitize transformed cells to metformin under conditions of energy stress.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».